Pharmaceutical substances may be introduced into a human or animal host for therapeutic or curative purposes in a number of ways. In many pharmaceutical applications, the pharmaceutical substance is administered in the form of solid particles. For example, a micropump may be used in some applications for prolonged treatment by slowly injecting a suspension of small particles in a liquid. Also, small particles having both a pharmaceutical substance and a biodegradable polymer may be placed within tissue for sustained release of the pharmaceutical substance, with the biodegradable polymer acting to control the release of the pharmaceutical substance. Furthermore, in pulmonary delivery applications, small particles may be inhaled to lodge in tissue of the lungs, permitting the pharmaceutical substance to then enter the circulatory system.
Often, however, problems are encountered in attempting to make particles having the desired properties for a particular pharmaceutical application. For example, when particles having a biodegradable polymer and a pharmaceutical substance are prepared, the pharmaceutical substance often concentrates near the surface of the particles. This effect may cause a sudden, undesirable release of the pharmaceutical substance when it is initially introduced into the host. Also, when using a micropump for continuous injection of a suspension over a prolonged period, the solid particles tend to settle over time, which may cause an undesirable variation in the rate of delivery of the pharmaceutical substance.
With respect to pulmonary delivery applications, current methods for delivering the pharmaceutical substance in small particles typically result in a majority of the pharmaceutical substance being wasted. In one method, called nebulization, a liquid having the pharmaceutical substance in solution is sprayed at a high velocity and inhaled. Alternatively, nebulization may involve spraying a powder as fine particles propelled by a carrier gas, with the particles being inhaled. Particles administered by both these nebulization methods, however, may have a wide distribution of droplet or particle sizes, resulting in a very low utilization of the pharmaceutical substance. Particles, or droplets, which are too large tend to lodge in the throat and mouth during inhalation and are not, therefore, effective for delivering the pharmaceutical substance to the lungs. Particles, or droplets, which are too small tend not to impact on the lung tissue, but rather tend to be exhaled. As much as 80 to 90 percent, or more, of the pharmaceutical substance may, therefore, be wasted and only a small portion of the pharmaceutical substance which is administered may actually reach the desired target in the lung.
Many of these problems with delivery of particles of a pharmaceutical substance result from limitations on methods used to make the particles. One method for making particles of a pharmaceutical substance, called lyophilization, involves rapid freezing of the pharmaceutical substance with water, followed by rapid dehydration of the frozen material to produce dry particles of the pharmaceutical substance. This technique has been used with proteins and other polypeptides, but the low temperatures involved may reduce the biological activity of some polypeptide molecules. Also, the particles produced by lyophilization tend to be large and clumping and are often not suitable for pharmaceutical delivery methods which require smaller particles. It is possible to grind the lyophilized particles to produce smaller particles, but such grinding may damage some pharmaceutical substances, especially proteins. Also, even when a substance may be ground without significant damage to the activity of the substance, it is difficult to obtain a pharmaceutical powder having particles of a narrow size distribution. Therefore, such pharmaceutical powders are prone to substantial waste of the pharmaceutical substance, such as described above for pulmonary delivery applications.
One method which has been proposed for making small particles of a pharmaceutical substance is called gas antisolvent precipitation. In this method, a pharmaceutical substance is dissolved in an organic solvent which is then sprayed into an antisolvent fluid, such as carbon dioxide, under supercritical conditions. The antisolvent fluid rapidly invades spray droplets, causing precipitation of very small pharmaceutical particles.
The gas antisolvent precipitation technique, however, requires that the pharmaceutical substance be soluble in the solvent. For hydrophobic pharmaceutical substances, this generally presents no problem because those substances can readily be dissolved in relatively mild, non-polar organic solvents. Hydrophilic pharmaceutical substances, however, are substantially insoluble in such relatively mild organic solvents.
It has been proposed that insulin, a hydrophilic protein, may be processed in a gas antisolvent precipitation process by dissolving the insulin in dimethylsulfoxide (DMSO) or N, N-dimethylformamide (DMF), both of which are strong, highly polar solvents. One problem with such a process, however, is that highly polar solvents such as DMSO and DMF tend to unfold protein molecules from their native tertiary structure, or conformation. These protein molecules would, therefore, also be precipitated in an unfolded state for incorporation into the solid particles. Such unfolding could seriously reduce the biological activity of a protein or other polypeptide, especially if stored as a solid particle in the unfolded state for any appreciable time.
There is a need for improved methods for making solid particles of pharmaceutical substances, and especially for making particles of hydrophilic substances, to permit preparation of particles having an appropriate size and size distribution without the molecular unfolding associated with the gas antisolvent precipitation method and without the low temperatures and grinding associated with lyophilization.